Tuberculosis endotypes to guide stratified host-directed therapy

Abstract

There is hope that host-directed therapy (HDT) for Tuberculosis (TB) can either shorten treatment duration, help cure drug resistant disease or limit the immunopathology. Many candidate HDT drugs have been proposed, however solid evidence only exists for a few select patient groups. The clinical presentation of TB is variable, with differences in severity, tissue pathology, and bacillary burden. TB clinical phenotypes likely determine the potential benefit of HDT. Underlying TB clinical phenotypes, there are TB "endotypes," defined as distinct molecular profiles, with specific metabolic, epigenetic, transcriptional, and immune phenotypes. TB endotypes can be characterized by either immunodeficiency or pathologic excessive inflammation. Additional factors, like comorbidities (HIV, diabetes, helminth infection), structural lung disease or Mycobacterial virulence also drive TB endotypes. Precise disease phenotyping, combined with in-depth immunologic and molecular profiling and multimodal omics integration, can identify TB endotypes, guide endotype-specific HDT, and improve TB outcomes, similar to advances in cancer medicine.

Keywords: Tuberculosis; endotypes; immune correlates of protection.

Figure 1:

Overview of immune response to Mtb infection 1. Dendritic cells (DCs), polymorphonuclear neutrophils (PMNs), and macrophages phagocytose Mtb leading to either mycobacterial survival or death. 2. DCs are professional antigen presenting cells and bring Mtb antigens to the draining lymph node, where DCsimplement antigen presentation and activation the classic CD4+ T cell response. 3. Macrophages are the preferred intracellular niche for Mtb. When activated by TNF and IFN-γ, they upregulate ROS, lysosomal acidification and phagolysosome maturation and increase Mtb killing capacity (More M1-like macrophage). When activated by IL-10, IL-4, IL-5 or IL-13, they down-regulate these processes, temper intracellular killing and focus on wound healing (More M2-like macrophage). Tissue macrophages represent a spectrum that typically includes elements of both M1 and M2 phenotypic characteristics. 4. Neutrophils, phagocytose and kill Mtb, but also produce cytokines and when they die, they spew out an extracellular matrix of chromatin and proteins that alert other immune cells. 5. CD4+ T cells produce cytokines, such as Th-1 cytokines TNF, IL-2 and IFN-γ that stimulate macrophages for intracellular killing, or Th2 cytokines IL-4, IL-5 and IL-13 that promote macrophage wound healing. 6. Cytotoxic T cells, as well as Natural Killer (NK) cells, MAIT (mucosal associated invariant T cells) and Innate LymphoidCells (ILCs), in addition to producing activating or suppressive cytokines, can induce perforin and granzyme-mediate cytotoxic killing of Mtb-infected cells. 7. B cells produce antibodies that neutralize extracellular Mtb, mediate NK CD16 antibody dependent cytotoxicity, and mark Mtb for opsonophagocytic clearance.

Figure 2:

Endotypes are the distinct host molecular pathways by which an individual can progress to TB. While some endotypes are exclusive, other endotypes overlap. For example, defects in the IL-12- IFN-γ axis (A) result in immune deficiency and overlap with the IFN-γ deficient endotype (B). Similar, after tonic antigenic stimulation, immune exhaustion (C) leads to deficiencies in both TNF and IFN-γ. A. IL-12- IFN-γ upstream defects in IL12, the IL12 receptor, IKKB or IRF8 result in decreased IFN-γ production and decreased mycobacterial killing capacity. In contrast, downstream defects in the IFN-γ receptor, STAT1 or IRF1 result in increased IFN-γ, but decreased IFN-γ signal transduction and decreased mycobacterial killing capacity. B. Host immunity has a narrow therapeutic window: deficiencies in TNF and IFN-γ result in decreased capacity to kill intracellular Mtb. In contrast, exuberant TNF and IFN-γ lead to macrophage necrosis and viable Mtb escape into the extracellular space. C. Short antigenic stimulation induces Warburg metabolism, increased glycolysis and glutaminolysis that triggers beneficial epigenetic immune changes. In contrast, chronic antigenic stimulation, either from TB itself, or from previous HIV, helminth or other chronic infection, results in tonic NFAT and mTOR activation resulting in metabolic and epigenetic mediated immune exhaustion. Immune exhaustion is characterized by decreased cytokine (TNF, IL-2 and IFN-γ) production, so this phenotype overlaps with above. D. Mycobacterial immunity requires both intact and well-balanced myeloid and lymphoid immunity. Hemophagocytic lymphohistiocytosis (HLH) represents imbalance, with deficient cytotoxic T cell and NK cell immunity and myeloid driven immunopathology with excessive TNF, IL-6 and phagocytosis. Likely, this overlaps with the exuberant phenotype depicted in B.

Figure 3:

Unbiased clustering of publicly available data allows for identification of gene expression derived clusters. Applying multimodal integration techniques, endotypes can be discovered and characterized based on the their metabolic, epigenetic, genetic and immune phenotype. Similarly, multimodal integration would clarify which epidemiologic factors are likely driving specific endotypes. Multimodal integration will identify the constellation of clinical epidemiology and biomarkers best suitable for treatment with putative HDT candidates that should be prospectively evaluated in umbrella and basket clinical trials.